Soluble amidine salts



Patented Nov. 5, 1946 SOLUBLE AMIDINE SALTS George Newbery, Brentwood,and Alexander Peter Tawse Easson, HornohurchEngland, assignors to May &Baker Limited, Dagenham, Essex, England, a British company No Drawing.Original application April 11,1942,

Serial No. 438,612. Divided and this application May 11, 1945, SerialNo. 593,326. In Can- 'Lada' April 77, .1942

" Claims.

This application is a division of application Serial No. 438,612, filedApril 11, 1942.

This invention relates to new salts of certain therapeutically-activeamidine derivatives and it has for its principal object the provision ofa new class of therapeutically active compounds that can be administeredin the form of an aqueous solution. A further object is toprovideprocesses for the production of such compounds.

-It vhas already been shown that valuable therapeutic properties arepossessed 'bythe symmetrical aromatic diamidines possessing the generalformula Am. R. X. R. Am,gin 'whichAmrepresents an amidine group Rrepresents a benzene radical; and X represents a linkage which may be asingle bond or an alkane chain (C H2)n (where .n represents 1 to andjinwhich also one'or more of the CH2 groups may be replaced byoxygen,sulphur or the group NH) orX represents a -.CR1=CR2- grouping in whichR1 and Breach represent either a'hydrogen atom or a hydrocarbon group(e. g; an alkyl, aryl or aralkyl group). Generally, the salts of thesediamidines, such as the hydrochlorides, are not very readily soluble inwater. "It is an obvious therapeutic advantage to have available stablesalts possessing a high degree of solubility in water and the presentinvention has, for its object the production of such salts. In manyinstances, therapeutically useful basic compounds have been found tofurnish extremely soluble salts with methane-sulphonates; but in thecase of the various therapeutically useful amidine compounds, such as4:-4'-.diamidino-stilbene or 4: 4diamidinoediphenoxypentane, thedimethane-sulphon'ates .are very little more soluble than the hydrochlorides.

We have discovered a new class of salts of the symmetrical aromaticdiamidines having the foregoing general formula, which salts are stableand possess a high degreeof solubility in water, such salts being thesalts with member-s of the group consisting of hydro-xy-ethane sulphonicacid and hydroxy-propane sulphonic acid.

In general, these new salts can be prepared by combining the diamidinebase or a salt thereof with hydroxy ethane 'sulphonic acid orhydroxypropane sulphonic acid or with a salt (of either of such acids.Specifically, the diamidine base can be directly combined withhydroxy-ethane or hydroxy-propane sulphonicxacid or with a suitable salt'of either of such acids (e. g. the-ammonium salt). Alternatively, therequired salts maybe'iformed by producingthe diamidin'e base in situ and.m the :presence -of ei-ther :one of the said acids or a salt of suchacid. Thus, the iminoether corresponding to the diamidin'e' base may bereacted with the amm'onium salt of hydroxyethane or" hydroxy-propanesulphoriic acid. Again, the required salts may be obtained by doubledecomposition of suitable salt pairs e. g. using the dihydrochlorideofthe diamidine base and the silver salt of the acid.

Examples of diamidines of the foregoinggener-al formula are:4:4-diamidino-diphenoxy pentane, 4:4-diamidino-dip'henoxy propane and4:4- diamidino-diphenyle'ther, 4 :4 -diamidino-'stilbene and 4 4-diamidino-a,u'-dimethyl-stilbene.

In the following description, there are given, purely byway ofillustration, examples of the manufactureof compounds Within thescope-of the present invention.

Example I 4:4-diamidino-stilbene (7.2 g.) was added to 6.8 cc. of 8Naqueous solution of ,B-hydroxyethane-sulphonic acid; the mixture warmedto about 40 C. and just sufficient water added'to complete solution..Acetone was then slowly added, when 4:4-diamidinosti1b'enedi-pehydroxyethane sulphonate (di-isethionate) crystallised in the formof prisms :(solubilityin water approx. 1 in Sat 20C.)

The corresponding di- -hydroxy-propane-isuh phonate is similarlyprepared (using the theoretical amount of -hydroxy-propane-sulphonicacid) and c-rystallises in prisms (solubility .in water approx; 1 in 4at 20C.) I

Example "II 4 :4 -diamidinodiphenoxy pentane-di-hydroxyethane-sulphonateprepared by the method of Example I, using the theoretical amounts ofthe diamidine-and the acid, crystallised as prisms on addition ofacetone to the aqueous solution. It contains 2 /2 H20 and is soluble inwater, approX. 1 in 8 at 20C.

Example II] Example I 67.2 grms. of 4:4'-diamidinodiphenylether weredissolved in a slight excess of 8N isethionic acid with sufiicientwaterto give complete solution in the cold. The solution was just acidto litmus, and to it was added about quarter of its volume of alcohol.Acetone was then added slowly and with stirring, so that the amidineisethionate separated in crystalline form. Addition was continued untilprecipitation was almost complete. The mixture was allowed to stand forsome time and the crystals filtered ofi, washed with acetone and dried.The yield of the required 4:4'-diamidinodiphenylether (ii-isethionatewas 130 grmS.

Example V 9.0 grins. of 4:4'-diamidino-a,a'-dimethylstilbenedihydrochloride were dissolved in a little warm water and slight excessof caustic soda solutionadded. The diamidine base was precipitated as anoil which solidified on cooling in ice. The base was filtered off,washed with water: and then while damp dissolved in a slight excess of8N isethionic acid. A little alcohol was added and the vrequired4:4'-diamidino-m,u'-dimethyl-stilbene di-isethionate precipitated in theform of buff yellow micro crystals. Yield 9.8 grms.

Example VI Example VII A mixture of stilbene 4:4-di-iminoethyl-ether(1.6 g.) and finely powdered ammonium e-hydroxy-ethane-sulphonate wassuspended in 5 cc. of absolute alcohol to which was added a few drops ofconcentrated alcoholic ammonia and the mixture brought to the boil. Mostof the ammonium salt dissolved and separation of the amidine isethionatefollowed in a few minutes. The temperature was maintained at 40 C. forapprox. hours with occasional shaking, acetone was then added and theprecipitated solid filtered ofi and dissolved in a little Water. Thesomewhat turbid solution was charcoaled, filtered and again treated withacetone. The required 4:4'-diamidino-stilbene-di-chydroxy ethanesulphonate crystallised out as in Example I.

Example VIII 37.3 grins. of pure 4:4'-diamidinostilbene dihydrochloridedihydrate (33.7 grms. of anhydrous salt) were dissolved in 400 cos. ofhot water and cipitated. The precipitate was filtered olT (char: 7

coal can be used if necessary to clarify), and the solids washed withwater. The filtrate and washings were concentrated by evaporation andthe required diamidine di-isethionate precipitated in crystalline formby adding a little alcohol, followed by the slow addition of acetonewith shaking, un-' til precipitation was complete. The yield obtainedwas 49 grms. of 95% of theory.

We claim: c 1.- 4:4'diamidino-diphenylether-di beta hy- 5droxyethane-sulphonate.

2. Process for the production of a symmetrical aromatic diamidine salthaving the formula in which X is selected from the group consisting of,hydroxy-ethyl and hydroxy-propyl radicals, which comprises reacting acompound of the for- 3=NH ('3=NH NH: NHQ

with a member selected from the group consisting ofbeta-hydroxyethane-sulphonic acid, gamma-hydroxy-propane-sulphonic acid,and the ammonium salt of a said acid.

3. A symmetrical compound of the formula in which X is selected from thegroup consisting of hydroXy-ethyl and hydroxy-propyl radicals.

4. Process for the production of 4:4'-diami- 45dino-diphenylether-di-beta-hydroxy-ethanesulphonate, which comprisesreacting 4:4'-diamidino-diphenylether with beta-hydroxy-ethanesulphonicacid.

. 5. Process for the production of a symmetrical 50 aromatic diamidinesalt having the formula in which X is selected from the group consistingof hydroxy-ethyl and hydroXy-propyl radi-' 0 cals, which comprisesreacting a symmetrical compound of the formula Q (I3=NH NH:

NHz

with a member selected from the group consisting ofbeta-hydroxy-ethane-sulphonic acid, gamma-hydroxy-propane-sulphonicacid, and the ammonium salt of a said acid.

GEORGE NEWBERY.

7s ALEXANDER PETER TAWSE EAssoN;

